Piperazine derivatives



2,858,313 Patented Oct..28, 1958 PIPERAZINE DERIVATIVES Stephen M. Olin, Elkhart, Ind., assignor to Miles Laboratories, Inc., Elkhart, Ind., a corporation of Indiana No Drawing. Application September 20, 1956 Serial No. 610,895

5 Claims. (Cl. 260-268) This invention relates to certain compounds possessing important physiological activity as hypotensives. More particularly, the invention relates to 1,4-unsymmetrically substituted piperazines derivatives having the following empirical formula:

wherein R is selected from the group consisting of furfuryl, cyclohexyl and an alkyl containing 4 to 5 carbon atoms. In addition to the free bases of these compounds, the acid addition salts such as the sulfate, the hydrochloride and like salts of these compounds are also within the specific contemplation of this invention.

Although wholly unexpected, when R is an alkyl group containing less than 4 or more than 5 carbon atoms, no perceptible antihypertensive activity is revealed in tests conducted with said compounds.

These tests were conducted on dogs caused to become hypertensive by methods known to the art. The LD/50 intraperitoneal dosage for mice of the compounds were determined by experimentation and the hypertensive dogs were injected intravenously with 2% of the dosage. At the end of 1 hour the blood pressure of the dogs was taken and thereafter an additional 3% .of the dosage was injected intravenously. At the end of a two hour period the blood pressure was again recorded and 5% of the dosage was injected. At the end of the third hour the blood pressure was again recorded. The average of the percentage of blood pressure decrease of the three readings was calculated and added to the percentage of blood pressure decrease at the end of the third hour. The mean of these two numbers which is considered to be directly proportional to the eilectiveness of the compositions as a hypotensive agent was as follows:

CHz-CH;

Where R is: Activity Furfuryl (CH C H 20 Cyclohexyl (-C H ll Iso-propyl (-C H 0 Z-methyl propyl (C H 36 Iso-amyl (C H 9 n-Hexyl (C H 0 Z-ethyl hexyl (C H 0 That reaction found to be productive of good yields of the claimed compounds involves the interaction of the appropriate N,N-bis(2-haloalkyl) tertiary amine with the appropriate primary amine as represented in the following:

This reaction forming the piperazine portion of the final compound will be described in greater detail after a re view of the preliminary preparation of the tertiary amine reactant.

CHzCHzOH CHzCHzOH This compound is prepared in excellent yield by the addition of ethylene oxide to an aqueous suspension of the nt-methylphenylethylamine. To this primary amine (1.0 mole) and 50 ml. of water at 50-60 C., ethylene oxide (2.2 moles) was passed in or added dropwise to the batch. At the end of the addition, the reaction mixture was distilled. The final product having a boiling point of 140l45/.l5 mm. and n D 1.529 was produced in a 92% yield.

On treatment with thionyl chloride, the hydroxyl groups in the two bis-hydroxyalkylamines are replaced by chlorine to give the N,N-bis(2-chloroalkyl) tertiary amines shown.

3 CH2OH2OI To a solution of the N,N-bis(2-hydroxyethyl) tertiary amine (1.0 mole) in 400 ml. of chloroform is added thionyl chloride (2.2 moles). The reaction mixture is refluxed until the evolution of gas has abated and the mixture then concentrated under reduced pressure. The residual hydrochloride is then either recrystallized without further treatment or converted to the free base by cold concentrated sodium hydroxide and extracted with toluene or xylene. However, this bis-chloro cornpound was found to be more conveniently handled and stored as the hydrochloride salt. A salt having a melting point of 190 was produced in 77% yield using ethanol as the crystallizing solvent. Theoretical chlorine content is 35.85% and that found by Parr bomb determination was 35.19%.

Returning to the final reaction first described, a mixture of the selected N,N-bis(2-chloroethyl)amine or its hydrochloride salt as prepared above is reacted with the selected primary amine to achieve the cyclization resulting in the piperazine ring. The reaction proceeds with or without solvent at temperatures in the range of 80 to 190.

In line with the foregoing, the following examples provide a description of the specific operations performed under the general methods described.

EXAMPLE I 1- (Z-methylpropyl) -4- (I-metlzyZ-Z-phenyle!hyl) piperazine N,N-bis- (2-chloroethyl -l -phenylpropylamine-2 (about 0.1 mole, free base formed from a water solution of the hydrochloride and excess sodium hydroxide and extracted with toluene), toluene ml.) and isobutylamine (22.0 g., 0.3 mole), were placed in a 250 ml. round-bottomed flask fitted with a thermometer and reflux condenser. The reaction mixture was refluxed for five hours, then it was combined with aqueous sodium hydroxide ml. of 2 N). The organic layer was separated and the aqueous layer was extracted with toluene (50 ml.). The organic layer and extract were combined, dried and concentrated. The residue was distilled under reduced pressure. 23.3 g. of l-(2-methylpropyl)-4-(1-methyl-2- phenylethyl)piperazine (90% yield) as obtained by this reaction had a boiling point of 106-108 at 0.15 mm. and refractive index 11 1) 1,508.

CHzCHzCl 175 which was unchanged on recrystallization from methanol and ethyl acetate. It was analyzed as 8.89% sulfur as compared to the theoretical 8.95%.

EXAMPLE H d-] -isamyl-4- I -methyl-2 -pheny le thyl piperazine In a 500 ml. round-bottom flash fitted with a reflux condenser were placed N,N-bis (2-chloroethyl) l-methyl- 2-phenylethyl (from dextroamphetamine) (59.3 g., 0.2 mole), isoamylamine (73 g., 0.84 mole) and xylene (200 ml.). The reaction mixture was refluxed for eighteen hours. To the cooled reaction mixture was added 125 ml. of aqueous sodium hydroxide The xylene layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was distilled. 29.8 grams of d-l-isoamyl-4-(1-methyl-2-phenylethyl)-piperazine (61% yield) as obtained by this reaction had a boiling point of 131132 at 0.35 mm. and refractive index N D 1.5085. It was analyzed at 10.22%

. nitrogen (perchloric titration as compared to the theoretical 10.21%).

The free base (13.4 g., 0.049 mole) Was dissolved in anhydrous ether and combined with ethereal hydrogen chloride. The precipitate was recrystallized from methanol-ethyl acetate to constant melting point, 292293, 11.1 g. (68% yield). It was analyzed at 20.49% chlorine (aq. titration) and 20.87% (Parr) as compared to the theoretical of 20.41%.

EXAMPLE III 1 -furfuyl-4-(1 -methyl-2-p-h enylethyl piperazine N,N-bis(2-chloroethyl)-1-methyl 2 phenylethylamine (29.6 g., 0.1 mole) and furfurylamine (29.1 g., 0.3 mole) were placed in a 250 ml. round-bottomed flask fitted with a reflux condenser, stirrer and thermometer. The reac tion mixture was heated slowly until an exothermic re action began (this Was at about 80 C.). The heater was withdrawn and the reaction was modified by cooling with an ice bath. The temperature rose to 170 before it began to fall. The ice bath was removed and the temperature of the reaction mixture was allowed to fall to 120. Heat was applied and the reaction mixture was maintained at 120-l30 for fifteen minutes. The reaction mixture was combined with sodium hydroxide (20 g., 0.5 mole) in water (100 ml.) and the resulting free base was extracted with ether. The ethereal solution was dried and concentrated. The residue was distilled under reduced pressure. 11.9 g. of 1-furfuryl-4- (1-methyl-2-phenylethyl)piperazine (40% of yield) as obtained by this reaction had a boiling point of 142-147 at 0.35 mm. and refractive index n D 1.545.

The free base (10.5 g., 0.036 mole) in ethanol (25 ml.) was added to a solution of hydrogen chloride (3.0 g.,

4 0.08 mole) in ethanol (50 ml.). The resulting precipitate was recrystallized from methanol. The yield obtained by thi reaction was 10.0 g. having a melting point of 252-253. The percent chlorine calculated for the dihydrochloride is 19.90 as compared to 19.66 found for the product.

In addition to the above compounds, the following has also been produced by the general method described and employed in the foregoing examples: l-cyclohexyll-(lmethyl-Zyhenylethyl)piperazine having a refractive index 22 of 1.535 and a boiling point of l40l50 at 0.1 mm. and melting as the sulfate salt at 225227.

These compounds in either the free base forms or as the salts can be conveniently employed in combination with the well-known pharmaceutical excipients such as elixirs or conventional tabletting compositions, for example.

The salts of the free bases are obtainable in the form of various acid addition salts as exemplified by the dihydrochlorides and the sulfates. The most satisfactory yields of the dihydrochloride, without undue development of the mono-hydrochloride, were obtained by adding a slight excess of a solution of anhydrous hydrogen chloride to a solution of the free base in solvent which would allow the salt to crystallize slowly and completely. Similarly, there is a problem arising from the hemisulfates in the preparation of the sulfates. However, the hemisulfates were intentionally prepared in an effort to produce a salt less acidic than the aqueous solutions of the sulfates and dihydrochlorides which exhibit a pH of 1 to 3. The hemisulfates in solution had a pH of from 3 to 3.5 which solutions could be adjusted to a slightly higher pH before the free base began to precipitate.

This application is a continuation in part of my copending application Serial No. 462,123, filed October 13, 1954, now abandoned.

What is claimed is:

1. A compound selected from the group consisting of 1,4-unsymmetrically substituted piperazines having the and pharmaceutically acceptable acid addition salts thereof wherein R is selected from the group consisting of furfuryl, cyclohexyl and alkyl containing 4 to 5 carbon atoms. 1

2. 1-(2-methylpropyl)-4-(1 methyl 2 phenylethyl)- piperazine.

3. 1-isoamyl-4-(1-methyl-2-phenylethyl)piperazine.

4. 1-cyclohexyl-4-(1-methyl-2-phenylethyl)piperazine.

5. 1-furfuryl-4-( l-methyl-Z-phenylethyl)piperazine.

References Cited in the file of this patent UNITED STATES PATENTS 2,415,785 Buck et a1. Feb. 11, 1947 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1,4-UNSYMMETRICALLY SUBSTITUTED PIPERAZINES HAVING THE FORMULA: 